Balance of Brain Oxytocin and Vasopressin: Implications For

Home , AVP gene, Oxytocin, Oxytocin (medication), Vasopressin

Opinion

Balance of brain oxytocin and

vasopressin: implications for anxiety,

depression, and social behaviors

1 2

Inga D. Neumann and Rainer Landgraf

Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg, Germany

Max Planck Institute of Psychiatry, Munich, Germany

Oxytocin and vasopressin are regulators of anxiety, ([5] for review of human data), for opposing effects of OXT

stress-coping, and sociality. They are released within and AVP on the ﬁne-tuned regulation of emotional behav-

hypothalamic and limbic areas from dendrites, axons, ior. Speciﬁcally, OXT exerts anxiolytic and antidepressive

and perikarya independently of, or coordinated with, effects, whereas AVP predominantly increases anxiety-

secretion from neurohypophysial terminals. Central oxy- and depression-related behaviors. We will therefore put

tocin exerts anxiolytic and antidepressive effects, where- forward the hypothesis that a dynamic balance between

as vasopressin tends to show anxiogenic and depressive the activities of brain OXT and AVP systems impacts upon

actions. Evidence from pharmacological and genetic hypothalamic and limbic circuitries involved in a broad

association studies conﬁrms their involvement in indi- spectrum of emotional behaviors extending to psychopa-

vidual variation of emotional traits extending to psycho- thology.

pathology. Based on their opposing effects on emotional

behaviors, we propose that a balanced activity of both Central release patterns of OXT and AVP: coordinated

brain neuropeptide systems is important for appropriate and independent secretion into blood

emotional behaviors. Shifting the balance between the Following their neuronal synthesis in the hypothalamic

neuropeptide systems towards oxytocin, by positive supraoptic (SON) and paraventricular (PVN) nuclei (OXT,

social stimuli and/or psychopharmacotherapy, may help AVP), or in regions of the limbic system (AVP), both

to improve emotional behaviors and reinstate mental neuropeptides are centrally released to regulate neuronal

health. processes in a spatially and temporally ﬁne-tuned manner.

As neurotransmitters, following release from axon term-

Introduction inals they contribute to the synaptic mode of rapid infor-

Over the past years, substantial progress has been mation processing via hard-wired neuronal connections

achieved with respect to our neurobiological understand- [1,8]. A complementary mode of OXT and AVP release is

ing of the link between anxiety and stress-coping, on the non-synaptically from dendritic, somatic, and non-termi-

one hand, and social behaviors on the other. A dynamic nal axonal regions of the neuronal membrane [1,9]

interplay of genetic, epigenetic, and environmental factors (Figure 1). Upon diffusion to nearby or remote receptors

orchestrates both individual behavioral variations and the via the extracellular ﬂuid (ECF) and ligand binding, the

etiology of anxiety- and depression-related disorders. De- association of the OXT receptor (OXTR) and the AVP

spite this progress, available treatment options are far receptor (AVPR) subtypes AVPR1A and AVPR1B with

from being mechanism-based, which explains the need speciﬁc intraneuronal signaling cascades determines their

for innovative therapeutic interventions. One focus of acute or long-term effects [10–12]. Whereas the quality of

modern psychiatric research for future therapies has been neuropeptide-induced effects is primarily determined by

on neuropeptide systems, with oxytocin (OXT) and argi- localization of their receptors in distinct, particularly hy-

nine vasopressin (AVP) featuring prominently in such pothalamic and limbic, brain areas [10], local concentra-

endeavors [1–5]. The synthesis and release of OXT and tion of the neuropeptide ligand in the ECF and receptor

AVP within the brain are driven by anxiogenic, stressful, density are the major determinants of the intensity and

and notably social (both positive and negative) stimuli duration of such actions. Importantly, OXT and AVP

[1,6]. In turn, once released, both neuropeptides are key actions may partly overlap, due to >85% homology be-

regulators of anxiety-related behavior, passive versus ac- tween their receptors, and this has both physiological and

tive stress-coping as an indicator of depression-like behav- pharmacological implications [13,14].

ior, and multiple aspects of social behavior [1–4,7]. Simultaneous microdialysis and blood sampling has pro-

We here discuss experimental evidence, primarily from vided evidence for both coordinated and independent

rodents, but with complementary data from human studies release of OXT and AVP within the brain, and from neuro-

hypophysial terminals into blood (Figure 1), and these seem

Corresponding author: Neumann, I.D. ([email protected]) to be both stimulus-dependent and peptide-speciﬁc [1,15].

Keywords: anxiety; depression; neuropeptide balance; oxytocin; social behavior;

Providing evidence for coordinated release, numerous

vasopressin

Opinion Trends in Neurosciences November 2012, Vol. 35, No. 11

Blood circulation

Blood-brain barrier ? Limbic regions ECF Brain OXTR

CSF Nasal PVN, AN OXT SON Socio- emotional ? behaviors

Key: Endogenous OXT Median eminence Exogenous OXT OXTR in brain and periphery Pituitary

Blood circulation

Peripheral OXTR Labor, milk ejection

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Figure 1. The brain oxytocin (OXT) system: neuronal projections, release, receptor-mediated effects, and external application. Physiologically, OXT is secreted as a

neurohormone into the bloodstream from axon terminals of magnocellular hypothalamic OXT neurons via neurohemal contacts within the posterior pituitary upon

stimulation (e.g., birth, suckling, stress). These neurons may also target brain (e.g., limbic) regions via axon collaterals [8]. In addition to release from axon terminals as a

neurotransmitter, central release of OXT as a neuromodulator was shown to occur from dendrites and perikarya [1,9], explaining basal and stimulated levels in the

extracellular fluid (ECF) of distinct brain regions, as well as spatially and temporally precise point-to-point signaling. Central release can occur both independently of, and

simultaneously with, peripheral secretion. Together with the regional distribution and density of OXT receptor (OXTR), the amount of locally released OXT largely

determines the activity of the brain OXT system, thus contributing to the regulation of emotional and social behaviors [7]. Brain OXT availability can be further raised by

intranasal administration of OXT; exogenous OXT reaches both the cerebrospinal fluid (CSF) of brain ventricles and the systemic circulation [110,111]. From CSF, synthetic

neuropeptides may readily diffuse through the ventricular ependyma into the ECF according to the concentration gradient; blood–brain barrier (BBB) transport (Box 1) may,

to some extent, augment brain neuropeptide levels in a concentration-dependent manner [1]. Although exemplified for the brain OXT system in this cartoon, there is

substantial evidence for a comparable neurobiology of the brain arginine vasopressin (AVP) system with respect to neuronal synthesis, central release, peripheral secretion,

and external application [1]. Abbreviation: AN, accessory magnocellular nuclei.

physiological stimuli trigger both central and peripheral Accordingly, changes in neuropeptide concentrations in

OXT release, including birth, suckling, sexual activity, human plasma, saliva, or urine in a behavioral context

and various forms of stress, with essentially synergistic need to be interpreted with caution. Uncertainties as to the

behavioral and physiological actions of centrally (maternal site and dynamics of central release, and whether altered

behavior, sexual behavior, anxiolysis, social preference, and levels reﬂect causes or consequences of behavioral altera-

recognition) and peripherally (labor, milk ejection, orgasm) tions, limit their plausibility. In contrast to the separation

released OXT, respectively [15,16]. Magnocellular OXT neu- of central from peripheral compartments by the blood–

rons projecting to the posterior pituitary, but also targeting brain barrier (BBB) (Box 1), these neuropeptides may

limbic regions via axon collaterals [8], may explain such readily diffuse between brain ECF and ventricular cere-

coordinated release. brospinal ﬂuid (CSF) (Figure 1). Therefore, quantiﬁcation

Although these ﬁndings speak in favor of plasma in the CSF provides at least a global measure of neuropep-

OXT as being a global biomarker of central OXT tide activity in the brain, and affords a more accurate

system activity, the temporal dynamics of central and reﬂection of central release patterns [1]. Importantly, in

peripheral release may substantially differ in a stimulus- any body ﬂuid, questions about the reliability of neuropep-

dependent way. Moreover, various stressors have been tide measurements must be raised. Until assays are

shown to trigger OXT (and AVP) release within hypo- strictly validated and standardized to detect bioavailable

thalamic and limbic regions, whereas neuropeptide neuropeptide, interpretation of data (particularly from

secretion into blood remains virtually unchanged commercial assays without extraction) remains vague at [1,15,16]. best.

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Opinion Trends in Neurosciences November 2012, Vol. 35, No. 11

Box 1. OXT, AVP, and the blood–brain barrier (BBB) loss-of-function studies on AVP and its AVPR1A and

AVPR1B subtypes. Speciﬁcally, central or peripheral

The BBB prevents endogenous neuropeptides, such as OXT and

administration of AVPR antagonists, local antisense

AVP, from crossing in physiologically relevant amounts. OXT/AVP

plasma levels are generally lower than those in the ECF, further targeting of AVPR1A, AVPR knockout mice, and adeno-

restricting diffusion from blood to brain. The separation of central viral vector-induced AVPR1A upregulation [28,34–38]

and peripheral compartments under physiological conditions

have conﬁrmed the anxiogenic effects of endogenous

coevolved with the functional divergence of neuropeptide effects

AVP. In a rat model of high (HAB) versus low (LAB)

in blood and brain. Indeed, there are primarily independent

anxiety-related behavior, representing natural extremes

physiological functions at peripheral (e.g., antidiuresis) and central

(socio-emotional behaviors) levels. In addition, coordinated and of trait anxiety, the AVP gene was identiﬁed as a candi-

possibly synergistic actions of peripheral and central neuropeptides

date gene for inborn anxiety [39]. As exempliﬁed in this

may occur following simultaneous release into both compartments

model, as well as in early-life stress approaches [40,41],

(e.g., during birth). Thus, instead of being merely a protective

hyperactivity of the AVP system severely disturbs the

structure, the BBB contributes to both independent and fine-tuned

coordinated neuropeptide regulation. However, it should be noted neuropeptide balance, thus shifting behavior along a

that exogenous neuropeptides may reach the brain parenchyma continuum towards hyperanxiety and passive coping

through the BBB in minute, but functionally significant, amounts (as

(Figure 3). Consequently, reinstatement of the OXT–

indicated in Figure 1).

AVP balance, and of emotional behavior, could be

achieved by either loss-of-function approaches targeting

the AVP system [36] or, alternatively, by chronic OXT

OXT and AVP: anxiety and social phobia treatment, as shown in HAB rats [4].

Brain OXT and AVP are important regulators of anxiety, With respect to social anxiety, the AVPR1A of the mouse

although usually in opposing directions. Once released in medial amygdala was suggested to mediate prosocial beha-

brain regions involved in stress and anxiety regulation, for viors, with an opposite, antisocial role for AVPR1B, em-

example in response to anxiogenic stimuli [1,15,16], OXT phasizing the potential utility of the AVPR1B antagonist

exerts anxiolytic effects and modulates neuronal functions SSR149415 in patients with social anxiety or social phobia

related to physiological stress responses, mainly at the [42]. However, an involvement of the OXT system cannot

levels of the PVN and amygdala [8,17–21]. Particularly entirely be excluded because SSR149415 has also been

intriguing is the reduction in emotional responsiveness shown to weakly bind to OXTR [13].

during periods of high activity of the endogenous OXT There is also general support for an anxiolytic effect of

system, such as during lactation [22] and sexual activity OXT in humans. For example, nursing mothers with

[23,24]. Acute or chronic central administration of synthet- higher OXT levels are more likely to describe positive mood

ic OXT in rodents, thereby increasing neuropeptide avail- states and reduced anxiety [43,44]. By contrast, women

ability in the ECF (Figure 1), conﬁrmed the anxiolytic and who were abused in childhood have lower OXT concentra-

stress-protective effects in various experimental settings tions in CSF and higher anxiety scores [45].

both in females and males [25–28]. Moreover, the brain In a plethora of human studies, intranasal adminis-

OXT system seems to be important for fear expression and tration of synthetic OXT is currently used to increase the

extinction, as shown in a rodent model of cued fear condi- availability of OXT in the brain ECF and, consequently,

tioning [8,29]. Behavioral data from transgenic mice lack- brain OXT system activity (Figure 1). Despite individual

ing either OXT or the OXTR provide further support for variations in OXT effectiveness [46], these studies sup-

involvement of the brain OXT system in anxiety regulation port the capacity of the neuropeptide to modulate anxi-

[14,30]. The OXTR-mediated acute anxiolytic effect of OXT ety circuitries, including reduced [47] and enhanced [48]

within the PVN requires the intracellular activation of amygdala reactivity to fearful faces in men and women,

signaling cascades, such as the mitogen-activated protein respectively, indicating gender-speciﬁc modulation of

kinase cascade, which may contribute to long-term behav- perceptual salience and the processing of social cues.

ioral adaptations via gene regulation [12,20]. Whereas there appears to be little effect of nasal OXT

It is worth emphasizing that OXT exerts various pro- on trait anxiety in healthy men [49], OXT was shown to

social effects [7,31] which may, in particular, contribute to attenuate anxiety and fear responses in social contexts

its anxiolytic effects in a social context. Naturally occurring [50] ([5,51,52] for review). Moreover, in patients suffer-

social approach and social preference behavior was shown ing from social anxiety disorder or autism, intranasal

to be strictly dependent on brain OXT in rats and mice, and OXT reduced several symptoms of social impairment

social anxiety prevents such behavior [32,33]. In a rodent [53–56].

model of social defeat-induced social phobia, central Supporting rodent studies, emotional effects of synthet-

administration of OXT reversed social avoidance and ic AVP in humans also include increased anxiety and fear

rescued social preference [33] (Figure 2). Thus, according responses. For example, autonomic and behavioral

to our hypothesis, activation of the brain OXT system, for responses to threatening faces were elevated upon intra-

example, by positive social stimuli or pharmacotherapy, nasal AVP [57]. Further, amygdala responses to similar

results in increased central OXT availability and a (local or socio-emotional stimulation were found to be associated

global) shift of the OXT–AVP balance towards the former, with genetic variations of AVPR1A [58] (Table 1). Although

thus resulting in reduced levels of general and social intranasal administration of AVP did not affect anxiety in

anxiety (Figure 3). healthy men [59], AVPR1B antagonists were shown to

In contrast to OXT, the brain AVP system mediates attenuate indices of anxiety and depression in animal

anxiogenic effects, as shown by a variety of gain- and models and depressed individuals [37,60].

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Opinion Trends in Neurosciences November 2012, Vol. 35, No. 11

* 120 *

(a) 90

30 Invesgaon me (s) me Invesgaon

Obje ct Social Vehicle OXTR-A AVPR1A-A Social preference test Key: Obje ct Social * 120 *

(b) 90

+ 30 Invesgaon me (s) me Invesgaon

Obje ct Social No defeat Defeat Defeat Social defeat Social preference test vehicle vehicle OXT

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Figure 2. Brain oxytocin (OXT) promotes social preference and reverses defeat-induced social phobia in rodents. (a) In the social preference test, social preference is

reflected by longer exploration of the small cage containing a conspecific (social stimulus) than an empty small cage (object stimulus). The naturally occurring social

preference is prevented by central administration of an OXT receptor (OXTR) antagonist (OXTR-A), but not of an arginine vasopressin receptor (AVPR) antagonist (AVPR1A-

A). (b) 30 min exposure to social defeat (20 min before social preference testing) prevents social preference and results in social avoidance in vehicle-treated rats. Social

phobia can be reversed by intracerebroventricular infusion of OXT 20 min before behavioral testing. *P < 0.01. Adapted, with permission, from [33].

OXT, AVP, and depression-like behavior but also to a depression-like phenotype, which could be

Due to the high degree of comorbidity between anxiety and normalized by long-term treatment with the antidepres-

depression disorders, common mediators are likely to un- sant paroxetine [70]. Analogously, both AVP and AVPR1A

derlie both conditions. Indeed, in addition to its anxiolytic mRNAs were found to be overexpressed, and the number of

effect, synthetic OXT was shown to shift stress-coping in AVP-expressing neurons increased in the PVN of de-

rodents towards a more active coping style, after either pressed patients [71,72]. Thus, shifting the neuropeptide

central or peripheral administration, indicating antide- balance towards OXT by inhibition of brain AVP might be

pressive-like effects ([4,61,62] for review). Further, there beneﬁcial also in depression (Figure 3). Accordingly, mod-

is preclinical and clinical evidence that OXT may also ulators of AVPR activity are potential therapeutic tools,

contribute to the improvement of other depression-related such as the AVPR1B antagonist SSR149415 with anxio-

symptoms, including sexual dysfunctions [63,64], sleep lytic, antidepressant, and stress-buffering effects

disturbances [65], and anhedonia ([4] for review). [37,42,73]. However, to date none of these drugs has

Another phenomenon possibly related to both depres- reached the market [38].

sion and central OXT is hippocampal neurogenesis, which

seems to be important for stress-coping and the buffering of Mechanisms of effects of OXT and AVP related to

depressive behavior [66]. OXT, but not AVP, was recently anxiety and depression

shown to stimulate neuronal growth and to rescue gluco- Multiple brain neurotransmitter and neuromodulator sys-

corticoid- or stress-induced suppression of neurogenesis in tems are presumed to interact at various brain levels to

the hippocampus of adult rats [67]. shape individual variations in emotionality. The mecha-

In depressed patients, evidence for an altered OXT nisms underlying anxiolytic and antidepressive effects of

system, as deduced from plasma and CSF levels, is limited OXT are likely to include interactions with monoaminergic,

and inconsistent [4,68]. Although increased OXT mRNA in particular the serotonergic, and corticotropin-releasing

expression and OXT immunoreactivity were found in post- factor (CRF) systems, both of which have been implicated in

mortem hypothalamic tissue from depressed patients [69], anxiety disorders and depression [2,72,74]. A subpopulation

several questions remain – for example, whether such of OXTR-expressing serotonergic neurons exists within the

alterations represent causes or consequence of the disor- raphe nucleus [75]; in turn, stimulation of serotonin release

der, and whether antidepressant treatment can normalize activates hypothalamic OXT neurons [76]. Moreover, in

such changes. female rhesus monkeys, both serotonin and OXT are poten-

Similarly to anxiety, brain AVP appears to modulate tial targets of estradiol, and as such are likely to mediate its

depression-like behavior in an opposite manner to OXT, in prosocial and anxiolytic effects [77,78]. Thus, OXT-based

other words, shifting it towards passive stress-coping. therapy might be an additional option to reverse the postu-

Indeed, in the above-mentioned HAB rats, AVP overex- lated deﬁcits in serotonergic (and possibly noradrenergic)

pression in the PVN not only contributed to hyperanxiety neurotransmission in depressed individuals, the more

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Opinion Trends in Neurosciences November 2012, Vol. 35, No. 11

(a) Studies on neuropeptide mechanisms have recently

• Genetic / epigenetic variation

been complemented by the demonstration that OXT and

• Social / physiological stimuli

AVP modulate anxiety responses and fear extinction in the

• Psychopharmacotherapy

central amygdala of rats in opposite manners, and target

distinct neuronal populations. Following local release,

OXT attenuated fear by acting on two major populations

Oxytocin of neurons of an inhibitory network, one inhibited by OXT,

Vasopressin but excited by AVP (via AVPR1A), the other being excited

by OXT but unresponsive to AVP [19,21]. These ﬁndings

Hypothalamic and limbic circuitries

suggest important functional implications of neuropeptide

balance not only at the behavioral but also neuronal net-

Anxiety work levels.

Similar mechanisms of OXT action are expected to

Active coping underlie the emotional and anti-stress effects seen in a

continuously rising number of human neuroimaging stud-

Passive coping (Depression)

ies after intranasal administration (Figures 1 and 3). For

(b) example, in OXTR risk allele carriers (rs53576A; Table 1)

who display deﬁcits in socio-behavioral domains, altera-

Extremes in behavior at ends of the continuum

tions in hypothalamic-amygdala coupling were found [82].

• Hyper-anxiety, anxiety disorders • Hypo-anxiety Along the same lines, intranasal OXT has been shown to

• Passive stress coping, depression • Active stress coping

potently alter activation of the amygdala and its coupling

• High stress susceptibility • Stress resiliance

to brainstem regions in response to social and threatening

stimuli [48,49]. Intranasal administration of AVP has been

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found to modulate the activity and connectivity patterns

Figure 3. Hypothetical model depicting the balance in brain oxytocin (OXT) and

within prefrontal cortex-amygdala regions, circuitries that

arginine vasopressin (AVP) systems activity and its implications for behavioral

regulation from mental health to psychopathology. (a) Although brain OXT acts as are implicated in threat perception, the processing of

an endogenous anxiolytic and antidepressive neuropeptide, AVP exerts anxiogenic anxiety/fear, and in social behaviors [59].

and depression-like effects. Consequently, the balanced activities of the brain OXT

and AVP systems may impact upon individual variations in anxiety and stress-

coping style, indicative of depression-related behavior, along a continuum. The OXT, AVP, and social behaviors

brain OXT/AVP systems activity in hypothalamic and limbic regions and, thus,

According to the social brain hypothesis, the need to adapt

neuropeptide balance is determined by genetic, epigenetic, physiological, social,

behaviorally to increasing social complexity has substan-

and other environmental (risk) factors and can be further modulated by

psychopharmacotherapy (e.g., by administration of selective receptor agonists tially contributed to the development of brain mass, cogni-

or antagonists). Shifting the OXT–AVP balance to the left, for example, by genetic

tive abilities, emotions, and language [83]. Brain OXT and

risk factors (Table 1) and/or by negative social cues early in life, resulting in

AVP, as well as their evolutionary ancestors, are major

reduced OXT system activity, is probably associated with increased anxiety-related

behavior and passive stress-coping, thus increasing the risk of psychopathology. A players in the complex orchestra shaping sociality, and this

neuropeptide imbalance can be reflected by reduced OXT and elevated AVP

impacts upon both anxiety and stress-coping [3,7,31]. Fol-

system activity, respectively, or both. Thus, shifting the OXT–AVP balance does not

lowing their central release, both OXT and AVP promote

necessarily mean reciprocal changes of both neuropeptide systems.

Pharmacologically, the neuropeptide balance may be shifted towards the right important aspects of social behavior, including social pref-

by intranasal application of synthetic OXT and increased brain OXT availability

erence (OXT) [33], maternal care, and aggression (OXT and

(Figure 1), thus promoting the anxiolytic, anti-depressive, stress-protective, and

AVP) [84,85], sexual behavior (OXT) [63], pair-bonding in

prosocial effects of the brain OXT system. (b) Examples from animal and human

studies for extremes in behavioral phenotypes at the ends of the anxiety/stress- monogamous species (OXT and AVP) [31,86,87], social

coping continuum; the middle range represents species-specific phenotypic

cognition (OXT and AVP) [88–90], and inter-male aggres-

variation.

sion (AVP) [91,92]. It is of note in this context that the high

levels of sociability observed in rats after 3,4 methylene-

because some effects of selective serotonin reuptake inhibi- dioxymethamphetamine (ecstasy) administration were

tors (SSRI) are thought to be mediated by OXT [77]. Sup- shown to be OXT-mediated [93].

porting this view, polymorphisms in the serotonin In contrast to mostly opposite effects of OXT and AVP on

transporter and OXTR genes have recently been shown to anxiety and depression-related behavior, as discussed

interact in healthy men and women, thereby inﬂuencing above, social behaviors are often regulated in the same

their vulnerability for psychopathology [79]. direction, as seen, for example, in the context of pair-

In addition to AVP, hyperactivity of the brain CRF bonding in monogamous voles (although in a sex- and

system has been linked to both passive stress-coping in region-dependent manner) [31], maternal behavior [85],

rodents, and stress-related disorders such as depression and social memory [88,90]. However, only the brain OXT

[2,60,80]. In support, CRF and CRF receptor 1 genes are system appears to be essential for social preference and for

overexpressed in the PVN of both HAB rats [39,70] and the avoidance of social anxiety as a prerequisite for social

depressed patients [71,72]. OXT actions may partly be interaction, because AVP lacks such effects [33] (Figure 2).

mediated via effects on hypothalamic CRF neurons [25], Also, the facilitation of social fear extinction by OXT seems

which express OXTR [81]. Thus, following its activation by to be a neuropeptide-speciﬁc effect [94].

social or rewarding stimuli, endogenous OXT may contrib- Human studies conﬁrm multiple prosocial effects of both

ute to the attenuation of anxiogenic, depressive, and stress OXT and AVP after intranasal administration in healthy

effects of CRF. subjects, as well as in patients with emotional or social

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Opinion Trends in Neurosciences November 2012, Vol. 35, No. 11

Table 1. Examples of genetic polymorphisms in genes encoding OXTR, AVPR1A, and AVP that are associated with emotional and a

social phenotypes

Gene/polymorphism Species Associated phenotypes Refs

Oxytocin receptor

rs53576 Humans Optimism, self-esteem, depression [124]

(SNP in the 3 intron Social support seeking [117]

of the OXTR gene)

Empathy, stress reactivity [125]

or haplotype including

Sensitive parenting [126]

rs53576

Prosocial temperament; variations [82]

in hypothalamic, amygdala/cingulate

structure and function

Emotional loneliness [127]

Behavioral manifestations of prosociality [128]

Autism [129]

rs2254298 Humans Volume, function, and connectivity of [113,130]

(SNP in the 3 intron hypothalamus and limbic brain regions;

of the OXTR gene) ethnically and sex-dependent effects

Susceptibility to anxiety, depression, autism [131,132]

Vasopressin receptor 1A

Length variation in tandem Voles Monogamy, partner preference; modiﬁed [31]

repeats in promoter region receptor expression and distribution;

phenotypic conﬁrmation in transgenic

mice and rats

RS1, RS3 Humans Autism, personality traits; differential [58]

(polymorphic microsatellite activation of amygdala

repeats near the promoter) Altruism, trust; levels of AVPR1A mRNA [133]

in post-mortem hippocampi

Partner bonding [134]

Haplotypes consisting of Humans Autism [135]

RS1, RS3, and an intronic microsatellite

Vasopressin

Deletion in LAB promoter Mice (F2 panel Anxiety-related behavior [136]

from HAB Â

LAB crosses)

Examples were selected based on reproducibility and functional conﬁrmation.

dysfunctions [5,57,95,96]. In this context, OXT is particu- psychopathologies [7]. Many other positive health effects

larly prominent in the processing of positive social stimuli of social support were described in animal and human

[49,52,97,98]. Opposing effects of OXT and AVP on social studies, for example on immunological and cardiovascular

recognition and socio-emotional perception have been de- functions [7,103,104]. It is noteworthy that even intense

scribed, with intranasal OXT elevating [48] and AVP social interaction of humans with their pets leads to elevated

impairing [99] mind-reading, respectively. Moreover, neu- plasma OXT [105], and this may give rise to some of the

ropeptide effects are nuanced, with a sizeable minority of beneﬁcial effects described above.

human studies showing that OXT can even produce anti- Conversely, interrupted or lack of social interactions –

social effects under particular conditions [46]. anticipated as psychosocial stress – have been associated

with increased anxiety, especially social anxiety, or depres-

Inﬂuence of the social environment on brain OXT and sion-like behavior in rodents [33,101,106]. Indeed, psycho-

AVP activity social stressors including adverse social experiences early

Positive and rewarding social stimuli (such as mother– in life cause alterations in the OXT and AVP systems

offspring or socio-sexual interactions, and social support), [40,42,101,107–109]. Similarly, in humans, emotional ne-

and negative social experiences (such as defeat, subordina- glect or child maltreatment increase the risk for mental

tion, or interruption of maternal care early in life), differen- disorders and, under particular conditions, have also been

tially affect both neuropeptide systems. This is reﬂected by shown to be accompanied by lower OXT concentrations in

alterations in the expression, release, and receptor binding CSF in adulthood [45].

of OXT/AVP within limbic regions and, partly, in plasma Overall, whereas activation of the OXT system with

OXT or AVP concentrations [15,41,42,100–102]. We propose simultaneous inhibition of the AVP system might be a

that in this way the social environment may contribute to promising therapeutic option to treat anxiety disorders

the modulation of the activity of the brain OXT and AVP and depression due to mostly opposite emotional effects

systems, with positive stimuli being likely to shift the [4,54,55] (Figure 3), the impact of neuropeptide balance for

balance towards OXT (Figure 3). Indeed, rodent and human social behavior is less clear. Particularly in the case of

studies suggest that reinforcing positive social interactions unidirectional neuropeptide effects (e.g., on social cogni-

is generally beneﬁcial for mental health, and improves tion), the situation is further complicated by potential

emotional stability and concomitantly protects against OXT/AVP (including antagonist [13]) cross-reactivity,

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Opinion Trends in Neurosciences November 2012, Vol. 35, No. 11

particularly at high dosages, due to the high extent of in socio-emotional behaviors [3]. Their complexity is fur-

receptor homology [14]. Whether this is relevant for human ther enhanced by gene–gene [79] and gene–environment

studies remains to be shown, given the low neuropeptide [117] interactions, including epigenetic modiﬁcations

dose that is likely to reach the brain compartment after shown to modify AVP expression by early-life stress in

intranasal administration [110,111]. In any case, the func- mice [41], and OXTR deﬁciency in autism [118]. Such

tional and structural overlap of the OXT and AVP systems modiﬁcations are particularly capable of complementing

emphasizes the complexity of the pharmacology involved association studies, linking them to an environmental

in developing neuropeptide-based selective psychophar- context [119].

macotherapies. Thus, both genetic and epigenetic variations are likely

to contribute to the activity of the brain OXT and AVP

Gender-dependent effects of OXT and AVP systems shaping individual anxiety- and depression-relat-

An important aspect of neuropeptide functions that balance ed behaviors and, consequently, the risk for psychopathol-

emotional behavior is the sexual dimorphism of OXT/AVP ogy (Figure 3).

systems, and this may underlie the higher incidence of

anxiety disorders and depression in women, and antisocial Neuropeptide balance in the regulation of emotional

behavior and autism in males [112]. Estrogens upregulate behaviors

OXT synthesis within the PVN and regulate OXTR expres- The opposing effects of brain OXT and AVP systems on

sion in the amygdala via estrogen a- and b-receptor actions, anxiety and depression-related neuronal functions and

respectively. Sexually dimorphic amygdala reactivity to behaviors, as discussed above, support our hypothesis that

intranasal OXT [48], and gender-dependent impact of ge- a dynamic balance of the activities of the brain OXT and

netic variations in the OXTR upon hypothalamic and amyg- AVP systems impacts upon emotional behaviors along a

dala volume and functional coupling [82,113,114], further continuum from mental health to psychopathology

support the hypothesis of sex-dependent activity of the brain (Figure 3). Accordingly, psychiatric disorders can be con-

OXT system. sidered as extremes of quantitative dimensions at the

In contrast to OXT, AVP is mainly inﬂuenced by testos- negative end of a given continuum [120], explaining

terone via androgen, but also estrogen, receptor-mediated why, for example, pathological anxiety may evolve from

mechanisms [115]. It remains to be shown, to which extent normal anxiety [121]. We hypothesize that this shift to-

such mechanisms contribute to sexually dimorphic effects wards psychopathology is, at least in part, due to an OXT–

of intranasal AVP on human social communication and AVP imbalance determined by negative environmental, in

strategies in stressful contexts [57]. particular negative social, stimuli, in concert with genetic

and epigenetic (risk) factors. Conversely, based on ﬁndings

Genes of the OXT and AVP systems in association that the brain OXT system can be activated by social

studies stimuli, we further extend this model and hypothesize that

The data described so far, suggesting reliable OXT and AVP positive social interactions have the potential to shift the

effects on socio-emotional behaviors, stand in contrast to neuropeptide balance towards OXT, thereby attenuating

how little is currently known about candidate genes under- anxiety- and depression-related behaviors (Figure 3).

lying such behaviors and psychiatric disorders [116]. One Importantly, our hypothesis of an OXT–AVP balance

approach that can shed light on the genes involved is to primarily linked to emotional behaviors does not mean that

associate polymorphic variations, particularly single nucle- increased signaling of one neuropeptide is necessarily

otide polymorphisms (SNPs), with variations in emotional linked to reduced signaling of the other (although such

and social behaviors. However, genetic associations gener- regulatory capacity has recently been shown, both at neu-

ally raise issues related to replicability and the functional ropeptide ligand [122] and receptor [123] levels). Instead, it

effects of SNPs. It is, for instance, generally unknown how suggests that hypoactivity of OXT and hyperactivity of AVP,

polymorphic variations translate into differential expres- alone or together, may underlie a shift to the left along the

sion and availability of brain neuropeptides and their recep- behavioral continuum (Figure 3). In this case, we speculate

tors. Therefore, the selected examples presented in Table 1 that, in addition to appropriate stimulation of the endoge-

include only polymorphisms (i) that have repeatedly been nous system, combined psychopharmacotherapy of both an

conﬁrmed to impact upon socio-emotional phenotypes, or (ii) OXTR agonist and AVPR antagonists may have the poten-

with functional/structural correlates based on expression tial to synergistically improve psychopathological behavior.

and neuroimaging genetics approaches. Social dysfunctions are key symptoms not only of social

The neuropeptide variants that have been most exten- anxiety disorders, but also of several psychopathologies,

sively studied in their relation to behavioral traits are including major depression, post-traumatic stress disor-

located in the OXTR and AVPR genes (Table 1). For exam- ders, schizophrenia, and autism. Because OXT and AVP

ple, the A allele of rs53576 of the human OXTR gene (AA, AG modulate multiple aspects of both emotionality and social-

genotypes relative to G/G homozygotes) and haplotypes ity, we further propose that a neuropeptide imbalance is

including this SNP confer particular risks for deﬁcits in also likely to contribute to social deﬁcits accompanying

socio-emotional domains. Compared with their receptors, psychopathologies.

however, less is known about behavioral implications of

genetic variations in neuropeptide genes (Table 1). Concluding remarks

Generally, single-gene associations are ultimately lim- Individual variations in anxiety- and depression-related

ited in their ability to explain large portions of variability behaviors are determined by the dynamic interplay of

655

Opinion Trends in Neurosciences November 2012, Vol. 35, No. 11

4 Slattery, D.A. and Neumann, I.D. (2010) Oxytocin and major

Box 2. Outstanding questions

depressive disorder: experimental and clinical evidence for links to

Despite accumulating knowledge about the neurobiology of brain aetiology and possible treatment. Pharmaceuticals 3, 702–724

OXT and AVP systems from preclinical and clinical studies, several 5 Meyer-Lindenberg, A. et al. (2011) Oxytocin and vasopressin in the

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neuropeptide levels and genetic risk factors, to assess central structure, function, and regulation. Physiol. Rev. 81, 629–683

neuropeptide activities, to diagnose an OXT–AVP imbalance, and 11 Viero, C. et al. (2010) Oxytocin: crossing the bridge between basic

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temporally adequate manner. Although future studies are

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required to reveal the characteristics of appropriate sti-

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the selection of potentially responsive patients for treat-

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